Imidazo(2,1-b)thiazoles and thiazolo(3,2-a)pyrimidines



United States Patent 3,507,868 IMIDAZO[2,1-b]THIAZOLES AND THIAZOL0[3,2-a]PYRIMlDINES Robert E. Manning, Mountain Lakes, N.J., assignor to Sandoz-Wander, Inc., Hanover, N.J., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 727,363, May 7, 1968. This application Oct. 21, 1968, Ser. No. 769,417

Int. Cl. C07d 51/46, 91/52 US. Cl. 260-25 14 Claims ABSTRACT OF THE DISCLOSURE Indeno, naphtho and benzocyclohep-ta imidazo thiazoles and indeno, naphtho and benzocyclohepta thiazolo pyrimidines, e.g., 2,3 dihydro-9H-indeno[2',l'12,3]imidazo [2,1 b] thiazole, 3,4,10,11 tetrahydro 2H naphtho [2',l':2,3]thiazolo[3,2 a]pyrimidine and 2,3,10,11 9H- hexahydro benzocyclohepta [5,6-d] irnidazo [2,1-b] thiazole are prepared. These compounds are useful as anorexics.

where m represents 1 or 2 and n represents 1, 2 or 3.

According to one aspect of the invention, novel compounds of the Formula I are prepared in accordance with the following reaction scheme:

(CH2)n where m and n are as defined above.

Compounds of Formula I are prepared from the compounds of Formula II or their acid addition salts by treatment with acid at about room temperature to about 100 C., conveniently at reflux temperature. The acid used may be a strong acid, for instance a strong mineral acid such as a hydrohalic acid, e.g., hydrochloric acid and hydrobromic acid, or sulfuric acid, phosphoric acid and the like. When a strong acid addition salt of the 3,507,868 Patented Apr. 21, 1970 compounds of Formula II is utilized, a weaker acid, e.g., acetic acid, propionic acid, and the like may be used. The above process always provides an acid addition salt of compounds of the Formula I, the particular salt made being dictated by the acid addition salt of Formula II utilized, if any, and the acid used for the dehydrolysis. Solvents such as lower alkanol, e.g., ethanol or isopropa- 1101, or water and the like may be used in connection with the above process. However, use of such solvent is not necessary and excess acid may be used in lieu thereof when the reactant (II) is sufiiciently soluble therein. Preferably, water as solvent is not utilized when a weak acid such as acetic acid is used. The solvents and temperatures mentioned above are not critical in obtaining the product (II). Conventional recovery techniques may be used.

The compounds of Formula II may be prepared in accordance with the following reaction scheme.

where X is bromo or chloro and m and n are as defined above. The product obtained from the above reaction is the hydrohalide acid addition salt of the compound of Formula II and is either the hydrobromide or hydrochloride depending upon the nature of X. The acid addition salt of the compound of Formula I or II is readily converted either to the free base by conventional techniques, e.g., by dissolution of the salt in water and precipitation using a base such as sodium hydroxide, or it may be converted to another acid addition salt by salification of the free base.

The compounds of Formula II are prepared by treating a compound of Formula IV, e.g., 2-bromoindan-lone, with a compound of Formula III, e.g., propylenethiourea, in solvent at a temperature of about 0 to about C., preferably about 20 to about 40 C. The solvents which may be utilized include acetone, alcohol such as lower alkanols, e.g., propanol or ethanol, or tetrahydrofuran and the like. The particular solvents and temperatures used are not critical in obtaining the product. The compounds of Formula II are recovered using conventional techniques.

The compounds of Formulas III and IV are known and may be prepared according to methods disclosed in the literature.

The compounds of Formula I are useful because they possess pharmacological activity in animals. More particularly the compounds have CNS activity, and are particularly useful as anorexics as indicated by their activity in rats given 25 mg. per kilogram of active compound and tested using the free feeding method described by Randall et a1. (J.P.E.T., 129:163, 1960). Furthermore, these compounds of Formula I may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzene-sulfonate and the like.

When so utilized, these compounds may be combined with a pharmaceutically acceptable carrier or adjuvant and may be administered orally or parenterally. For this use, the dosage will vary depending upon the mode of administration utilized and the particular compound employed. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from about 1-20 mg. per kilogram of animal body weight, preferably given in divided doses, e.g., 2 to 4 times a day or in sustained release form. For most large mammals the total daily dosage is from about 5-150 mg. Suitable dosage forms comprise from about 1.25 mg. to about 75 mg. of the active compound in admixture with solid or liquid pharmaceutically acceptable carrier or diluents.

A representative formulation suitable for oral administration is a tablet prepared by standard tabletting techniques which contains the following.

Ingredient: Parts by Weight 2,3,9,10 tetrahydro naphtho [2',1':2,3]imidazo [2,1-b]thiazole Tragacanth 2 Lactose 79.5

Corn starch 5 Talcum 3 Magnesium stearate 0.5

EXAMPLE 1 4a-hydroxy-2, 3 ,9,9a-tetrahydro-4aH-indeno[2,1':2,3] imidazo[2,1-b]thiazole hydrobromide HBr To a suspension of ethylenethiourea (4.8 g.) in acetone (250 ml.) is added 2-bromoindan-1-one (9.45 g.) and the resultant mixture is stirred 36 hours. The resultant solid is collected by filtration to give 13.7 g. of 4a-hydroxy- 2,3,9,9a tetrahydro 4aI-I indeno[2,1':2,3]imidazo- [2,1-b]thiazole hydrobromide; M.P. 173-175 C.

EXAMPLE 2 2,3-dihydro 9H-indeno [2, 1' 2,3 ]imidazo[2,1-b] thiazole hydrochloride 4 EXAMPLE 3 5a-hydroxy-3 ,4,10,10a-tetrahydro-ZH,SaI-I-indeno- [2,1' 2,3]thiazolo [3,2-a] pyrimidine hydrobromide A j) S I HBr EXAMPLE 4 3,4-dihydro-2H, IOH-indeno [2, 1 2,3 thiazolo [3 ,2-a] pyrimidine hydrochloride HCl A mixture of 5a hydroxy-3,4,10,10a-tetrahydro-2H, 5aH-indeno[2',1:2,3]thiazo1o[3,2-a]pyrimidine (7.0 g.), methanol ml.) and concentrated hydrochloric acid (20 ml.) is refluxed 72 hours. The solution is evaporated in vacuo and the residue crystallized from methanol-ether (1:3) to give 5.2 g. of 3,4 dihydro 2H,10H-indeno- [2,1':2,3]thiazolo[3,2-a1pyrimidine hydrochloride; M.P. 310-312 C. with decomposition.

EXAMPLE 5 4a-hydroxy-2,3,4a,9,10, IOa-hexahydro naphtho[2',1:2,3] imidazo[2,1-b] thiazole hydrobromide iii 3 e HBr A solution of 2-bromo-1-tetralone (13.0 g.) in acetone (50 ml.) is added to a stirred suspension of ethylenethiourea (5.9 g.) in acetone (200 1111.). The reaction mixture is stirred for 48 hours and the resultant solid is collected by filtration to afford 13.8 g. of 4a-hydroxy-2,3,4a,9;10, IOa-hexahydro naphtho[2',1':2,3]imidazo[2,1-b]thiazole hydrobromide; M.P. 255256 C.

EXAMPLE 6 2,3,9,10-tetrahydro-naphtho[2',1' 2,3]imidazo [2, l-b] thiazole hydrochloride A mixture of 4a-hydroxy-2,3,4a,9,10,IOa-hexahydronaptho[2',1':2,3]imidazo[2,1-'b]thiazole (7.5 g.), methanol (100 ml.) and concentrated hydrochloric acid (20 ml.) is refluxed for 72 hours. The solution is evaporated and the residue crystallized from methanol-ether (1:3) to give 7.8 g. of 2,3,9,IO-tetrahydro-naphtho[2',1':2,3]imid azo[2,1-b]thiazole hydrochloride; M.P. 249-25 6 C. with decomposition.

EXAMPLE 7 a-hydroxy-3,4,5a,10,l1,1 1a-hexahydro-2H-naphtho- [2, 1:2,3 thiazolo [3,2-a] pyrimidine hydrobromide A solution of 2-bromo-1-tetralone (13.00 g.) in acetone (50 ml.) is added to a stirred suspension of propylenethiourea (6.7 g.) in acetone (200 ml.) and the resultant mixture is stirred for 48 hours. The resultant solid is collected by filtration to afford 19.5 g. of Sa-hydroxy- 3,4,5a,10,11,1la-hexahydro 2H naphtho[2,1:2,3]thiazolo[3,2-a]pyrimidine hydrobromide; M.P. 261-263 C.

EXAMPLE 8 3,4,10,1l-tetrahydro-ZH-naphtho[2',1':2,3]thiazolo- [3,2-a] pyrimidine hydrochloride e HCl A mixture of 5a-hydroxy-3,4,5a,10,11,11a-hexahydro- 2H--naphtho[2',1'z2,3]thiazolo[3,2-a]pyrimidine (9.5 g.), methanol (100 ml.) and concentrated hydrochloric acid (20 ml.) is refluxed for 7 hours. The solution is evaporated in vacuo and the residue is crystallized from methanolether (1:3) to give 9.9 g. of 3,4,10,11-tetrahydro-2H-naphtho[2',1:2,3]thiazolo[3,2 a]pyrimidine hydrochloride; M.P. 26 l263 C. with decomposition.

EXAMPLE 9 4a-hydroxy-2,3,9, l 0,1 1,1 1a-hexahydro-4aHbenzocyclohepta[5,6-d]imidazo[2,1-b1thiazole hydrobromide 5a hydroxy 3,4,10,11,12,1Za-hexahydro-ZH,SaH-benzocyclohepta- S,6':4,5 thiazolo 3,2-a] pyrimidine hydrobromide When the process described in Example 3 is carried When the process described in Example 2 is carried out and 4a hydroxy 2,3,9,10,11,11a hexahydro-4aH- benzocyclohepta[5,6-d]imidazo[2,1-b]thiazole is used in place or 4a-hydroxy-2,3,9,9a-tetrahydro-4aH-indeno[2, l:2,3]imidazo[2,1-b]thiazole, the title compound is ob tained; M.P. 266267 C.

EXAMPLE 12 3,4,1 1,12-tetrahydro-2H,10H-benzocyclohepta[5,6:4,5] thiazolo [3,2-a]pyrimidine hydrochloride When the process described in Example 2 is carried out and 5a-hydroxy-3,4,10,11,12,12a-hexahydro-2H,5aH- benzocyclohepta [5,6':4,5]thiazolo[3,2-a]pyrimidine is used in place of 4a-hydroxy-2,3,9,9a-tetrahydro-4aH- indeno[2'1:2,3]imidazo[2,1-b]thiazole, the title compound is obtained; 270271 C.

What is claimed is:

1. A compound of the formula "=N(CH2)m where m represents 1 or 2, and n represents 1, 2 or 3,

or a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim 1 which is 2,3- dihydro-9H-indeno[2',1':2,3]imidazo[2,1-b]thiazole or a pharmaceutically acceptable acid addition salt thereof.

3. A compound according to claim 1 which is 3,4- dihydro-2H,IOH-indeno[2,1:2,3]thiazolo[3,2 a] pyrimidine or a pharmaceutically acceptable acid addition salt thereof.

4. A compound according to claim 1 which is 2,3,9,10- tetrahydro-naphthol[2',1:2,3]imidazo[2,1 b]thiazole or a pharmaceutically acceptable acid addition salt thereof.

5. A compound according to claim 1 which is 3,4,10,11- tetrahydro 2H naphtho[2,1':2,3]thiazolo[3,2-a]pyrimidine or a pharmaceutically acceptable acid addition salt thereof.

6. A compound according to claim 1 which is 2,3,10,11- hexahydro 7 9H benzocyclohepta[5,6-d]imidazo[2,1-b] thiazole or a phermaceutically acceptable acid addition salt thereof.

7. A compound according to claim 1 which is 3,4,11,12- tetrahydro 2H,10H benzocyclohepta[5,6':4,5]thiazolo [3,2-a] pyrimidine or a pharmaceutically acceptable acid addition salt thereof.

8. A compound of the formula where m represents 1 or 2, and n represents 1, 2 or 3,

8 droxy 2,3,4a-9,10,l0a hexahydro naphtho[2',1:2,3] imidazo[2,lb]thiazole or an acid addition salt thereof.

12. A compound according to claim 8 which is Sa-hydroxy 3,4,5a,10,11,11a hexahydro 2H naphtho[2',1': 2,3]thiazo1o[3,2-a] pyrimidine or an acid addition salt thereof.

13. A compound according to claim 8 which is 4a-hydroxy 2,3,9,10,11,11a hexahydro 4aH benzocyclohepta[5,6-d]imidazo[2,1-b]thiazole or an acid addition salt thereof.

14. A compound according to claim 8 which is Sa-hydroxy 3,4,10,11,12,12a hexahydro 2H,5aH benzocyclohepta[5',6:4,5 ]thiazolo[3,2-a] pyrimidine or an acid addition salt thereof.

References Cited UNITED STATES PATENTS 3,169,970 2/1965 Snyder 260-3068 ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner -U.S. Cl. X.R. 

